Bioactive integration and stimuli-responsive therapeutic regulation in additively manufactured metallic orthopedic implants

Additive manufacturing (AM) has accelerated the evolution of metallic orthopedic implants from passive structural substitutes toward multifunctional therapeutic platforms. Leveraging the geometric freedom and compositional flexibility of AM, bioactive substances can be integrated into metallic implants through multiple strategies to regulate the peri-implant microenvironment and enhance tissue regeneration. This review summarizes recent advances in bioactive integration and responsive therapeutic release in additively manufactured metallic orthopedic implants. First, major biofunctionalization strategies are discussed, including surface modification, bulk alloying, and structurally integrated reservoirs. These approaches enable the incorporation of antibacterial, osteogenic, angiogenic, and immunomodulatory functions through localized delivery of antibiotics, bioactive ions, peptides, growth factors, and small-molecule therapeutics. Subsequently, recent progress in stimuli-responsive release systems is reviewed, including endogenous stimuli such as pH, enzymes, and reactive oxygen species, as well as exogenous stimuli such as light, magnetic fields, and electrical stimulation, which enable on-demand and microenvironment-adaptive therapy. The relationships among implant architecture, bioactive integration, and dynamic therapeutic regulation are further discussed to highlight the unique advantages of AM in constructing multifunctional implants. Finally, current challenges associated with multifunctional AM metallic implants are discussed, particularly the need to achieve synergistic biofunctionality, maintain structural and mechanical integrity under process constraints, ensure predictable therapeutic release, and establish reliable process–structure–property relationships. This review provides insights into the development of intelligent metallic implants that simultaneously provide mechanical support and actively regulate therapy.